The broad research aim for Dr. Quindry is to find solutions for preventing/lessening the impact of heart attacks using a model of exercise. These experiments will assess whether elevated mitochondrial KATP channel activity is an essential protective component of the exercised heart. A brief study rationale follows: Endurance exercise training is cardioprotective against all forms of ischemia- reperfusion (IR) injury including arrhythmia, stunning, and cell death. The specific mechanisms responsible for exercise-induced cardioprotection remain unclear. Based on previous work by our group and others, it appears that cardioprotection afforded by exercise is mediated at the mitochondrial level, specifically the mitochondrial KATP channel (mito KATP). Our working hypothesis is that the exercise-induced cardioprotection against IR insults is critically dependent upon an increase in myocardial mito KATP channel activity. Our proposed experiments, using a rat model of in vivo IR infarction, will provide a rigorous test of this hypothesis by addressing the following specific aims. Aim #1: We will determine if the exercise-induced increase in myocardial mito KATP activity is required for exercise-mediated protection against short duration IR-induced arrhythmia. To test this aim we will inhibit the exercise-induced increase in mito KATP channel activity by administration of a selective pharmacologic inhibitor for this channel. Hearts from exercised and sedentary animals will be exposed to in vivo short duration IR and ECG arrhythmias observed and recorded. Comparisons of ECG severity and magnitude will be performed between exercise trained (with, without inhibitor) and sedentary groups. Aim #2: We will determine if the exercise-induced increase in myocardial mito KATP activity is required for protection against IR infarction-induced necrosis and apoptosis in the exercised heart. To test this aim, we will inhibit the exercise-induced increase in mito KATP channel activity by administration of a selective pharmacologic inhibitor for this channel. Hearts from exercised and sedentary animals will then undergo long duration in vivo IR. The magnitude of necrotic and apoptotic cell death will be compared between exercised (with and without inhibitor) and sedentary animals. Relevance of findings: These proposed experiments will significantly advance the current understanding of why the exercised heart muscle is protected against heart attack damage. The near immediate applicability of these findings to humans further illustrates the value of these proposed experiments. This project will examine a novel component of heart attack protection in the exercised heart muscle. The impact of this work will provide a better understanding of heart physiology and biochemistry during a heart attack stress. More importantly, this work has the potential to significantly improve current lifestyle and pharmaceutical interventions against debilitating heart damage in the event of myocardial infarction. [unreadable] [unreadable] [unreadable]